The present invention relates to certain novel pyrimidinone compounds, processes for their preparation, intermediates useful in their preparation, pharmaceutical compositions containing them and their use in therapy, in particular in the treatment of atherosclerosis.
WO 95/00649 (SmithKline Beecham plc) describe the phospholipase A2 enzyme Lipoprotein Associated Phospholipase A2 (Lp-PLA2), the sequence. isolation and purification thereof, isolated nucleic acids encoding the enzyme, and recombinant host cells transformed with DNA encoding the enzyme. Suggested therapeutic uses for inhibitors of the enzyme included atherosclerosis, diabetes, rheumatoid arthritis, stroke, myocardial infarction, reperfusion injury and acute and chronic inflammation. A subsequent publication from the same group further describes this enzyme (Tew D et al, Arterioscler Thromb Vas Biol 1996:16:591-9) wherein it is referred to as LDL-PLA2. A later patent application (WO 95/09921, Icos Corporation) and a related publication in Nature (Tjoelker et al, vol 374, Apr. 6, 1995, 549) describe the enzyme PAF-AH which has essentially the same sequence as Lp-PLA2 and suggest that it may have potential as a therapeutic protein for regulating pathological inflammatory events.
It has been shown that Lp-PLA2 is responsible for the conversion of phosphatidylcholine to lysophosphatidylcholine, during the conversion of low density lipoprotein (LDL) to its oxidised form. The enzyme is known to hydrolyse the sn-2 ester of the oxidised phosphatidylcholine to give lysophosphatidylcholine and an oxidatively modified fatty acid. Both products of Lp-PLA2 action are biologically active with lysophosphatidylcholine, a component of oxidised LDL, known to be a potent chemoattractant for circulating monocytes. As such, lysophosphatidylcholine is thought play a significant role in atherosclerosis by being responsible for the accumulation of cells loaded with cholesterol ester in the arteries. Inhibition of the Lp-PLA2 enzyme would therefore be expected to stop the build up of these macrophage enriched lesions (by inhibition of the formation of lysophosphatidylcholine and oxidised free fatty acids) and so be useful in the treatment of atherosclerosis.
The increased lysophosphatidylcholine content of oxidatively modified LDL is also thought to be responsible for the endothelial dysfunction observed in patients with atherosclerosis. Inhibitors of Lp-PLA2 could therefore prove beneficial in the treatment of this phenomenon. An Lp-PLA2 inhibitor could also find utility in other disease states that exhibit endothelial dysfunction including diabetes, hypertension, angina pectoris and after ischaemia and reperfusion.
In addition, Lp-PLA2 inhibitors may also have a general application in any disorder that involves activated monocytes, macrophages or lymphocytes, as all of these cell types express Lp-PLA2. Examples of such disorders include psoriasis.
Furthermore, Lp-PLA2 inhibitors may also have a general application in any disorder that involves lipid peroxidation in conjunction with Lp-PLA2 activity to produce the two injurious products, lysophosphatidylcholine and oxidatively modified fatty acids. Such conditions include the aforementioned conditions atherosclerosis, diabetes, rheumatoid arthritis, stroke, myocardial infarction, reperfusion injury and acute and chronic inflammation. Further such conditions include various neuropsychiatric disorders such as schizophrenia (see Psychopharmacology Bulletin, 31, 159-165, 1995).
Patent applications WO 96/12963, WO 96/13484, WO 96119451, WO 97/02242, WO 97/217675, WO 97/217676, WO 96/41098, and WO 97/41099 (SmithKline Beecham plc) disclose inter alia various series of 4-thionyl/sulfinyl/sulfonyl azetidinone compounds which are inhibitors of the enzyme Lp-PLA2. These are irreversible, acylating inhibitors (Tew et al, Biochemistry, 37, 10087, 1998). GB 1 582 527 describes, as compounds of formula (7), a group of pyrimidone compounds of the formula (A): 
in which Alk is lower alkyl, Het is selected from 2- or 4-imidazolyl, 2-pyridyl, 2-thiazolyl, 3-isothiazolyl, 1,2,5-thiadiazolyl and n is from 1 to 4. These compounds are said to be useful as intermediates in the preparation of further compounds which are H2 antagonists.
A new class of pyrimidone compounds has now been identified which are inhibitors of the enzyme Lp-PLA2.
Accordingly, the present invention provides compounds of formula (I): 
in which:
Z is a bond and R1 is halogen; or
Z is CR3R4, where R3 and R4 are each hydrogen or C(1-4)alkyl, or R3 and R4 together with the intervening carbon atom form a C(3-6)cycloalkyl ring; and
R1 is an aryl or heteroaryl group, optionally substituted by 1, 2, 3 or 4 substituents selected from C(1-18)alkyl, C(1-18)alkoxy, C(1-18)alkylthio, arylC(1-18)alkoxy, oxo, hydroxy, halogen, CN, COR5, COOR5, CONR5R6, NR5COR6, SO2NR5R6, NR5SO2R6, NR5R6, mono to perfluoro-C(1-4)alkyl and mono to perfluoro-C(1-4)alkoxy;
X is O or S;
Y is a group of formula xe2x80x94A1xe2x80x94A2xe2x88x92A3xe2x80x94 in which A1 and A3 each represent a bond or a straight chain or branched C(1-10)alkylene group and A2 represents a bond or O, S, SO, SO2, CO, Cxe2x95x90CH2, CHxe2x95x90CH , Cxe2x89xa1C, CONH, NHCO, or CR5R6, providing that when A2 is O, S, SO, SO2 or CONH, A3 contains at least two carbon atoms linking the A2 group and the CH2 group in formula (I);
R2 is an aryl or heteroaryl group, optionally substituted by 1, 2, 3 or 4 substituents selected from the substituents hereinbefore defined for R1, as well as aryl and arylC(1-4)alkyl,
W is a bond and R7 is hydrogen; or
W is SO2 or a bond; and
R7 is R1 or a hydrocarbyl group which hydrocarbyl group may be optionally interupted within the carbon chain by a group selected from O, COO, OCO, CO, CONR8, NR8CO, NR8CONR9, NR8COO, OCONR8, and NR8, and which hydrocarbyl group may also be optionally substituted by 1 or 2 substituents selected from mono to perfluoro-C(1-4)alkyl, OR8, COOR8, CONR8R9, NR8COR9, NR8CONR9R10, NR8COOR9, OCONR8R9, NR11R12 and R1;
R5 and R6 are independently hydrogen or C(1-20)alkyl, for instance C(1-4)alkyl (e.g. methyl or ethyl);
R8, R9 and R10 are independently selected from hydrogen, C(1-20)alkyl (for instance C(1-15)alkyl), (which may optionally be fluorinated, including up to perfluorinated on the terminal 1 to 3 carbon atoms), C(1-20)alkenyl (preferably C(12-18)alkenyl), aryl, arylC(1-10)alkyl, C(1-10)alkoxyC(1-10)alkyl, or aryloxyC(1-10)alkyl and in which an aryl group may have one or two substituents selected from halogen, C(1-20)alkyl, C(1-20)alkoxy, aryloxy and COOC(1-20)alkyl; and
R11 and R12 are independently selected from one of the values hereinbefore defined for R8 and R9 or R11 and R12 together with the nitrogen atom to which they are attached form a 5- to 7 membered ring optionally containing one or two further heteroatoms selected from oxygen, nitrogen and sulphur, and optionally substituted by one or two substituents selected from hydroxy, oxo, C(1-4)alkyl, phenyl, or benzyl.
Preferably, Z is CH2.
Representative examples of R1 when an aryl group include phenyl and naphthyl. Representative examples of R1 when a heteroaryl group include pyridyl, pyrimidyl, pyrazolyl, furyl, thienyl, thiazolyl, quinolyl, benzothiazolyl, pyridazolyl and pyrazinyl.
Preferably R1 is a 5- or 6-membered, monocyclic heteroaryl group containing 1 or 2 nitrogen heteroatoms, preferably pyridyl, pyrimidyl or pyrazolyl, more preferably, pyrid-4-yl or pyrimid-5-yl and optionally substituted by 1 or 2 substituents preferably selected from arylC(1-4)alkyl (e.g. benzyl), C(1-8)alkyl (e.g. methyl or ethyl), halogen (e.g. chlorine), oxo, hydroxy, C(1-4)alkoxy (e.g. methoxy) and arylC(1-4)alkoxy (e.g. benzyloxy). More preferably, R1 is pyrimid-5-yl or a 2-oxo-pyrimid-5-yl group, optionally substituted at N-1 by C(1-8)alkyl (e.g. undecyl, methyl or ethyl), or a 2-C(1-4)alkoxy- or arylC(1-4)alkoxy-pyrimid-5-yl group.
Preferably, ZR1 is 2-oxo-pyrid-4-ylmethyl, pyrimid-5-ylmethyl or 2-oxo-pyrimid-5-ylmethyl in which the 2-oxo-pyrimid-5-yl moiety is as hereinbefore defined.
Preferably X is S.
Preferred compounds of formula (I) include those in which Y is a bond, i.e. A1, A2 and A3 each represent a bond. Other preferred examples of the groups A1 and A3 are straight chain C(1-10)alkylene groups. When A2 is other than a bond, A1 is preferably a bond. Preferred examples of A2 when other than a bond include CO, Cxe2x95x90CH2 and O, the CO group being especially preferred. Other preferred examples of Y are (CH2)7 and CO(CH2)6.
Representative examples of R2 when an aryl group include phenyl and naphthyl. Representative examples of R2 when a heteroaryl group include pyridyl, pyrimidinyl, pyrazolyl, furanyl, thienyl, thiazolyl, quinolyl,benzothiazolyl, pyridazolyl and pyrazinyl Preferably, R2 is phenyl optionally substituted by 1, 2 or 3 substituents selected from halogen (e.g. chlorine or fluorine), C(1-4)alkyl (e.g. methyl or ethyl) or C(1-4)alkoxy (e.g. methoxy). Further optional substituents include phenyl and benzyl.
Representative examples of R2YCH2X include 4-fluorobenzylthiogroup, 4-chlorophenylheptylthio and 4-chlorophenyl-1-oxaheptylthio. Preferably, R2YCH2X is 4-fluorobenzylthio group.
Preferably W is a bond.
Representative examples of R7 when a hydrocarbyl group include C(1-20)alkyl, C(2-20)alkenyl, C(2-20)alkynyl, C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-5)alkyl, or C(1-15)alkoxyC(1-10)alkyl each of which may be optionally substituted by 1 or 2 substituents as hereinbefore defined.
Preferably, W is a bond and R7 is C(1-20)alkyl, especially C(10-20)alkyl. Preferably, R7 is also C(1-10)alkyl, more preferably a C(1-6)alkyl which is substituted by one or two substituents selected from hydroxy, C(1-10)alkoxy (e.g. methoxy), COOC(1-10)alkyl (e.g. COOCH3, COOC2H5), CONR8R9, NR8CONR9R10, NHCOR8 (in which R8, R9 and R10 is each independently C(1-20)alkyl e.g. methyl). Further optional substituents include aryl, preferably phenyl which may be optionally substituted by COOC(1-6)alkyl (e.g methyl) and heteroaryl (for instance pyridyl, imidazolyl, furanyl, thienyl and 2-oxo pyrrolidinyl). Preferred examples of the substituent NR11R12 include morpholino, piperidino or 2-oxo-pyrrolidino group.
A preferred sub-group of compounds of formula (I) are those in which W is a bond and R7 is a phenyl or a phenylC(1-8)alkyl group, for instance benzyl or phenethyl, substituted in the phenyl ring by 1 or 2 substituents selected from C(6-12)alkyl (for instance hexyl and decyl), C(6-12)alkoxy, COOH, COOC(6-12)alkyl and CONHC(6-12)alkyl. Alternatively, R7 maybe heteroarylC(1-8)alkyl, preferably heteroarylC(1-3)alkyl in which the heteroaryl ring is monocyclic with 5 to 6 members and one or two heteroatoms selected from nitrogen, oxygen and sulphur, such as pyridyl, furanyl, thienyl and imidazolyl. A further preferred subgroup of compounds of formula (I) are those in which W is a bond and R7 is a group of the formula (CH2)nBR13 where n is an integer from 1 to 6, preferably 1 to 4, B is selected from NR14CO, CONR14, NR14CONR15, NR15COO (in which R14 and R15 are independently selected from hydrogen or C(1-6)alkyl, preferably hydrogen) and R13 is C(8-18)alkyl (which may optionally be fluorinated, including up to perfluorinated on the terminal 1 to 3 carbon atoms), C(8-18)alkenyl, phenyl C(1-6)alkyl and phenylC(1-8)alkoxyC(1-6)alkyl in which phenyl may be optionally substituted by halogen or C(1-6)alkyl. Prefered examples of C(8-18)alkyl are straight chains and include octyl, dodecyl and fatty alkyl groups such as lauryl and stearyl. Preferred values of C(8-18)alkenyl include octadec-9-(Z)-en-1yl. Preferred examples of optionally substituted phenylC(1-6)alkyl and phenylC(1-8)alkoxyC(1-6)alkyl include 4-fluorophenylhexyl, 4-pentylphenylethyl and 4-fluorophenylhexoxyethyl. Particularly preferred compounds of formula (I) are those in which R12 is C(12-18)alkyl or C(12-18)alkenyl. Such a long, lipophilic substituent is found to be especially beneficial for enzyme inhibition
When used herein, the term xe2x80x98alkylxe2x80x99 and similar terms such as xe2x80x98alkoxyxe2x80x99 includes all straight chain and branched isomers. Representative examples thereof include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, t-butyl, n-pentyl and n-hexyl.
When used herein, the term xe2x80x9chydrocarbylxe2x80x9d refers to a group having from 1 to 20 carbon atoms which may be in a straight chain or a branched chain and include a saturated carbocyclic ring having from 3 to 6 carbon atoms and which chain may contain unsaturation (double and/or triple carbon-carbon bonds).
When used herein, the term xe2x80x98arylxe2x80x99 refers to, unless otherwise defined, a mono- or bicyclic aromatic ring system containing up to 10 carbon atoms in the ring system, for instance phenyl or naphthyl.
When used herein, the term xe2x80x98heteroarylxe2x80x99 refers to a mono- or bicyclic heteroaromatic ring system comprising up to four, preferably 1 or 2, heteroatoms each selected from oxygen, nitrogen and sulphur. Each ring may have from 4 to 7, preferably 5 or 6, ring atoms. A bicyclic heteroaromatic ring system may include a carbocyclic ring. Representative examples include pyridyl, pyridyl N-oxide, pyrimidyl, pyrazolyl, furyl, thienyl, thiazolyl, pyridazolyl and pyrazinyl, quinolyl and benzothiazolyl.
When used herein, the terms xe2x80x98halogenxe2x80x99 and xe2x80x98haloxe2x80x99 include fluorine, chlorine, bromine and iodine and fluoro, chloro, bromo and iodo, respectively. Compounds of formula (I) are inhibitors of Lp-PLA2 and as such are expected to be of use in treating atherosclerosis and the other disease conditions noted elsewhere. Such compounds are found to act as inhibitors of Lp-PLA2 in in vitro assays
Particularly preferred compounds of formula (I) are
2-(4-Fluorobenzylthio)-5-((pyrimid-5-yl)methyl)pyrimidin-4-one;
1-Methyl-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(Tetradec-1-ylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one;
1-(N-(Dodec-1-yl)-N-methylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(pyrimid-5-ylmethyl)pyrimidin-4-one; and
1-(N-Methyl-N-(dodec-1-yl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(2-methoxypyrimid-5-ylmethyl)pyrimidin-4-one.
Since the compounds of the present invention, in particular compounds of formula (I), are intended for use in pharmaceutical compositions, it will be understood that they are each provided in substantially pure form, for example at least 50% pure, more suitably at least 75% pure and preferably at least 95% pure (% are on a wt/wt basis). Impure preparations of the compounds of formula (I) may be used for preparing the more pure forms used in the pharmaceutical compositions. Although the purity of intermediate compounds of the present invention is less critical, it will be readily understood that the substantially pure form is preferred as for the compounds of formula (I). Preferably, whenever possible, the compounds of the present invention are obtained in crystalline form.
When some of the compounds of this invention are allowed to crystallise or are recrystallised from organic solvents, solvent of crystallisation may be present in the crystalline product. This invention includes within its scope such solvates. Similarly, some of the compounds of this invention may be crystallised or recrystallised from solvents containing water. In such cases water of hydration may be formed. This invention includes within its scope stoichiometric hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilisation. In addition, different crystallisation conditions may lead to the formation of different polymorphic forms of crystalline products. This invention includes within its scope all polymorphic forms of the compounds of formula (I).
Compounds of the present invention are inhibitors of the enzyme lipoprotein associated phospholipase A2 (Lp-PLA2)and as such are expected to be of use in therapy, in particular in the treatment of atherosclerosis. In a further aspect therefore the present invention provides a compound of formula (I) for use in therapy. The compounds of formula (I) are inhibitors of lysophosphatidylcholine production by Lp-PLA2 and may therefore also have a general application in any disorder that involves endothelial dysfunction, for example atherosclerosis, diabetes, hypertension, angina pectoris and after ischaemia and reperfusion. In addition, compounds of formula (I) may have a general application in any disorder that involves lipid peroxidation in conjunction with enzyme activity, for example in addition to conditions such as atherosclerosis and diabetes, other conditions such as rheumatoid arthritis, stroke, inflammatory conditions of the brain such as Alzheimer""s Disease, myocardial infarction, reperfusion injury, sepsis, and acute and chronic inflammation. Further such conditions include various neuropsychiatric disorders such as schizophrenia (see Psychopharmacology Bulletin, 31, 159-165, 1995).
Further applications include any disorder that involves activated monocytes, macrophages or lymphocytes, as all of these cell types express Lp-PLA2. Examples of such disorders include psoriasis.
Accordingly, in a further aspect, the present invention provides for a method of treating a disease state associated with activity of the enzyme Lp-PLA2 which method involves treating a patient in need thereof with a therapeutically effective amount of an inhibitor of the enzyme. The disease state may be associated with the increased involvement of monocytes, macrophages or lymphocytes: with the formation of lysophosphatidylcholine and oxidised free fatty acids: with lipid peroxidation in conjunction with Lp PLA2 activity; or with endothelial dysfunction.
Compounds of the present invention may also be of use in treating the above mentioned disease states in combination with anti-hyperlipidaemic or anti-atherosclerotic or anti-diabetic or anti-anginal or anti-inflammatory or anti-hypertension agents. Examples of the above include cholesterol synthesis inhibitors such as statins, anti-oxidants such as probucol, insulin sensitisers, calcium channel antagonists, and anti-inflammatory drugs such as NSAIDs.
In therapeutic use, the compounds of the present invention are usually administered in a standard pharmaceutical composition. The present invention therefore provides, in a further aspect, a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier. Suitable pharmaceutical compositions include those which are adapted for oral or parenteral administration or as a suppository.
Suitable pharmaceutical compositions include those which are adapted for oral or parenteral administration or as a suppository. Compounds of formula (I) which are active when given orally can be formulated as liquids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges. A liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suspending agent, preservative, flavouring or colouring agent. A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose. A composition in the form of a capsule can be prepared using routine encapsulation procedures. For example, pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule. Typical parenteral compositions consist of a solution or suspension of the compound of formula (I) in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil. Alternatively, the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration. A typical suppository formulation comprises a compound of formula (I) which is active when administered in this way, with a binding and/or lubricating agent such as polymeric glycols, gelatins or cocoa butter or other low melting vegetable or synthetic waxes or fats.
Preferably the composition is in unit dose form such as a tablet or capsule. Each dosage unit for oral administration contains preferably from 1 to 500 mg (and for parenteral administration contains preferably from 0.1 to 25 mg) of a compound of the formula (I). The daily dosage regimen for an adult patient may be, for example, an oral dose of between 1 mg and 1000 mg, preferably between 1 mg and 500 mg, or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, preferably between 0.1 mg and 25 mg, of the compound of the formula (I), the compound being administered 1 to 4 times per day. Suitably the compounds will be administered for a period of continuous therapy, for example for a week or more.
Compounds of formula (I) may be conveniently prepared from readily available starting materials by adapting synthetic methodology well known in the art for the preparation and derivatisation of pyrimidones by a process.
Accordingly, in a first aspect, the present invention provides a process for preparing a compound of formula (I) which process comprises:
(a) treating a compound of formula (IIA): 
xe2x80x83which R1 and Z are as hereinbefore defined; with a compound of formula (III):
R2YCH2L1xe2x80x83xe2x80x83(III)
in which Y and R2 are as hereinbefore defined and L1 is a leaving group e.g. bromine or iodine; to give a compound of formula (IA): 
in which Z, Y, R1 and R2 are as hereinbefore defined and X is S; or
(b) treating a compound of formula (IV): 
in which Z and R1 are as hereinbefore defined and L2 is a leaving, group, e.g. halogen such as chlorine or bromine, alkylthio such as methylthio, or xe2x80x94NHNO2, with a compound of formula (V):
R2YCH2XHxe2x80x83xe2x80x83(V)
in which X, Y and R2 are as hereinbefore defined; advantageously at an elevated temperature, in a solvent such as pyridine, to give a compound of formula (IA); and thereafter, and if so desired;
treating, a compound of formula (IA) form (a) or (b) above with a compound of formula (VI):
R7WL1xe2x80x83xe2x80x83(VI)
in which L1, W and R7 are as hereinbefore defined; to give a compound of formula (IB): 
in which X, Y, Z, R1 and R2 are as hereinbefore defined and WR7 is as hereinbefore defined, other than xe2x80x94H; or
(c) treating a compound of formula (IIB): 
in which W is a bond, Z and R1 are as hereinbefore defined and R7 are as hereinbefore defined, other then H,
with a compound of formula (III) as hereinbefore defined, to obtain a compound of formula (IB); and, thereafter and if so desired;
treating a compound of formula (IA) or (IB) in which X is S with a compound of formula (V):
R2YCH2OHxe2x80x83xe2x80x83(VII)
in which Y and R2 are as hereinbefore defined;
to give a corresponding compound of formula (I) in which X is O.
In the above process, the reaction of the compounds of formulae (IIA/B) and (III) is advantageously effected in the presence of a base such as sodium ethoxide, potassium carbonate, preferably in a solvent such as ethanol or dimethylformamide, or a base such as di-isopropyl ethylamine, preferably in a solvent such as dichloromethane.
In the above process, the reaction of the compounds of formulae (IA) and (VI) is advantageously effected at a temperature of 20-100 degrees C., in the presence of sodium hydride in a solvent such as dimethylformamide; or by the compound of formula (IA) being pre-treated with tributyl tin chloride in the presence of di-isopropylethylamine, for example in a dichloromethane solvent at reflux temperature, followed by addition of (VI) Alternatively, the compound of formula (IA) may be treated directly with a compound of formula (VI) and di-isopropylethylamine in a dichloromethane solvent at room temperature.
In the above processes, the reaction of the compounds of formulae (IA/IB) and (VII) is conveniently effected in the presence of pyridine at an elevated temperature, containing a catalytic amount of 4-dimethylaminopyridine.
A compound of formula (I) in which Z is a bond and R1 represents halogen may be obtained by treating a compound of formula (VIII): 
in which W, Y, R2, and R7 are as hereinbefore defined; with a halogenating agent, preferably with bromine to form a compound of formula (I) in which Z is a bond and R1 is bromine, the reaction being advantageously effected in a solvent such as dichloromethane.
A compound of formula (IIA) may be obtained from a compound of formula (IX):
L3OCOCH2ZR1xe2x80x83xe2x80x83(IX)
in which L3 is C(1-6)alkyl, for instance methyl, and Z and R1 are as hereinbefore defined;
by the initial treatment thereof with a formylating agent such ethyl formate in the presence of a strong base such as potassium t-butoxide or sodium hydride, to give an enolate metal salt compound of formula (X): 
in which L3, Z and R1 are as hereinbefore defined and M is a metal cation, for instance sodium or potassium. Further treatment of a compound of formula (X) or a salt thereof with thiourea leads to a compound of formula (IIA). The two steps, starting form the compound of formula (IX) may conveniently be carried out as a xe2x80x9cone-potxe2x80x9d process.
A compound of formula (IIB) may be obtained from a compound of formula (X), in a series of steps. In a first step, a compound of formula (X) is converted into the corresponding methyl enol ether by treatment with a methylating agent such as dimethyl sulphate in the presence of a base such as potassium carbonate. The corresponding carboxylic acid may then be obtained by conventional hydrolysis, for instance basic hydrolysis, using, for instance aqueous sodium hydroxide. The acid may then be converted into the corresponding acyl chloride, by treatment with oxalyl chloride, and the acyl chloride treated with potassium thiocyanate in a solvent such as acetonitrile, to give an intermediate of the formula (XI): 
in which R1 and Z are as hereinbefore defined. Treatment of a compound of formula (XI) with a compound of formula (XII):
R7WNH2xe2x80x83xe2x80x83(XII)
in which R7 is as hereinbefore defined and W is a bond, followed by the addition of an organic base such as sodium ethoxide, leads to a compound of formula (IIB).
A compound of formula (IV) in which L2 is N(H)NO2 can be conveniently prepared by reacting a compound of formula (X) above with a compound of formula (XIII): 
in which the reaction is carried out in a conventional manner.
A compound of formula (VIII) may be obtained by treating a 3,3-dialkoxypropionic ester of the formula (XIV):
(L3)O2CCH2CH(OL3)2xe2x80x83xe2x80x83(XIV)
in which L3 is as hereinbefore defined;
with a thiourea of the formula (XV):
R7NHCSNH2xe2x80x83xe2x80x83(XV)
in which R7 is as hereinbefore defined;
in the presence of sodium hydride followed by aqueous acetic acid.
Compounds of formula (I) in which R7 comprises an amide moiety can be prepared from a precursor comprising an ester, for instance a methyl or ethyl ester, by first converting the ester to an acid, by hydrolysis and then treating the acid with an appropriate amine, under amide bond forming conditions. The acid may preferably be converted into an activated derivative, prior to amide bond formation.
Compounds of formula (I) in which R7 comprises a urea moiety can be prepared from a precursor comprising an amine moiety, by treating the amine with an isocyanate, under urea forming conditions, well known in the art.